ORGANIC LETTERS
Application of a Raney-Cobalt-Mediated Tandem Reductive Cyclization Protocol to Total Syntheses of the Aspidosperma Alkaloids (()-Limaspermidine and (()-1-Acetylaspidoalbidine
2012 Vol. 14, No. 22 5621–5623
Shen H. Tan, Martin G. Banwell,* Anthony C. Willis, and Tristan A. Reekie Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra ACT 0200, Australia
[email protected] Received September 27, 2012
ABSTRACT
The racemic modification of the Aspidosperma alkaloid limaspermidine (1) has been prepared in ten steps including one involving a Raneycobalt-mediated tandem reductive cyclization of nitrile 8 to give the tetracyclic system 9b. Compound (()-1 has been converted over two steps into (()-1-acetylaspidoalbidine [(()-13].
The natural product limaspermidine (1, Figure 1) was isolated from the trunk bark of the small tree A. rhombeosignatum MARKGRAF found growing in the Venezuelan Amazonas1 and shown to be the C21-hydroxylated derivative of the more well-known alkaloid aspidospermidine.2 The racemic modification of compound 1 was first described by Ban et al. in the mid-1970s3 and served as an advanced intermediate in that group’s landmark synthesis of (()-fendleridine (2).3,4 It also served as an advanced intermediate in Overman’s 1991 synthesis of compound 2.5 Our own interest in compound 1 and certain related systems stems from their potential to serve as precursors to a range of alkaloids including those of the aspidofractinine, (1) Medina, J. D.; Di Genova, L. Planta Med. 1979, 37, 165. (2) For details of the most recent synthesis of this alkaloid as well as useful background material, see: Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Nature 2011, 475, 183. (3) Honma, Y.; Ohnuma, T.; Ban, Y. Heterocycles 1976, 5, 47. (4) For the second and enantioselective synthesis of this alkaloid, see: Campbell, E. L.; Zuhl, A. M.; Liu, C. M.; Boger, D. L. J. Am. Chem. Soc. 2010, 132, 3009. (5) Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Am. Chem. Soc. 1991, 113, 2598.
Figure 1. Structures of limaspermidine and fendleridine.
kopsine, and vincadifformine series.6 Accordingly, we now report a novel synthesis of it wherein the B- and D-rings are formed in a tandem reductive cyclization process that is mediated, in a remarkably chemo- and stereoselective fashion, by hydrogen in the presence of Raney-cobalt.7 (6) Saxton, J. E. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, 1998; Vol. 50, p 343. (7) For previous applications of Raney-cobalt to the selective reduction of nitriles, see: (a) White, L. V.; Schwartz, B. D.; Banwell, M. G.; Willis, A. C. J. Org. Chem. 2011, 76, 6250 and references therein. (b) Kukula, P.; Studer, M.; Blaser, H.-U. Adv. Synth. Catal. 2004, 346, 1487. 10.1021/ol3026846
r 2012 American Chemical Society Published on Web 10/30/2012
This work emphasizes the particularly effective manner in which this activated alloy can selectively bring about the reduction of nitrogen-containing functionalities, especially nitro and nitrile units, in the presence of other potentially reactive groups, especially ketones, alkenes, and enamines. The reaction sequence leading to (()-limaspermidine [(()-1] is shown in Scheme 1 and starts with the alkenyl oxirane 3, a compound that is easily prepared from 2-cyclohexenone via nucleophilic epoxidation and methylenation of the 7-oxabicyclo[4.1.0]heptan-2-one so-formed.8 Treatment of substrate 3 with the readily available xanthate NCCH2SC(S)OEt in the presence of triethylborane and oxygen led, via a free-radical addition process,9 to the 2-cyclohexen-1-ol 4 (74%) that engaged in an Eschenmoser Claisen rearrangement10 on treatment with the dimethylacetal of N,N-dimethylacetamide in refluxing toluene. The product cyclohexene-amide 5 (80%), now incorporating a quaternary carbon center, was subjected to allylic oxidation with manganese triacetate/tert-butylhydroperoxide under conditions reported by Shing et al.11 The product 2-cyclohexen-1-one 6 (74%) was subjected to Johnsontype iodination,12 and the resulting iodide 7 (73%) engaged in a Pd[0]-catalyzed Ullmann cross-coupling reaction13 with o-nitroiodobenzene, thus providing the R-arylated cyclohexenone 8 (85%), the substrate required for the Raney-cobalt-mediated tandem reductive cyclization reaction. In the pivotal step, compound 8 was exposed to a large excess of freshly prepared Raney-cobalt in MeOH with 5 mol equiv of p-TsOH at 40 °C. A chromatographically separable mixture of indole 9b (85%) and its N-hydroxy counterpart 9a (variable yields) was thereby obtained, and the structures of both of these products were established by single-crystal X-ray analyses.14 The ORTEP derived from the latter analysis is shown in Figure 2. Resubjection of the compound 9a to the reductive cyclization conditions resulted in the generation of additional quantities of congener 9b, while running the original process at higher temperatures and/or for extended reaction times resulted in the exclusive formation of the former product (9b) in 85% yield. There are several rather interesting features to the conversion 8 f 9b. In particular, the exclusive formation of the cis-ring fused product 9b over its (presumably) more stable trans-configured counterpart suggests that the cyclization event leading to D-ring formation is a kinetically controlled process. Furthermore, it appears that the (8) Welker, M.; Woodward, S.; Alexakis, A. Org. Lett. 2010, 12, 576. (9) Charrier, N.; Gravestock, D.; Zard, S. Z. Angew. Chem., Int. Ed. 2006, 45, 6520. (10) Linton, E. C.; Kozlowski, M. C. J. Am. Chem. Soc. 2008, 130, 16162 and references therein. (11) Shing, T. K. M.; Yeung, Y.-Y.; Su, P. L. Org. Lett. 2006, 8, 3149. (12) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.; Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett. 1992, 33, 917. (13) Banwell, M. G.; Jones, M. T.; Reekie, T. A. Chemistry in New Zealand 2011, 75, 122. (14) CCDC 894937894939 contain the crystallographic data for 1, 9b, and 9a, respectively. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif. 5622
Scheme 1. Total Synthesis of Limaspermidine [(()-1]
cyclization process leading to B-ring formation proceeds, at least to some degree, through the hydroxylamine derived from reduction of the nitro group in substrate 8. With amide 9b in hand the completion of the synthesis of (()-limaspermidine (1) proved relatively straightforward. Thus, the former compound served as the substrate for an Org. Lett., Vol. 14, No. 22, 2012
Scheme 2. Conversion of (()-Limaspermidine [(()-1] into (()-1-Acetylaspidoalbidine [(()-13]
Figure 2. ORTEP derived from the single-crystal X-ray analysis of compound 9a with labeling of selected atoms. Anisotropic displacement ellipsoids display 30% probability levels. Hydrogen atoms are drawn as circles with small radii.
E-ring annulation protocol introduced by Toczko and Heathcock.15 Specifically, amide 9b was treated with R-chloroacetyl chloride in the presence of triethylamine, and the resulting acylated compound 10 (60%) was subjected to a Finkelstein reaction using sodium iodide in acetone, thus affording congener 11 that upon treatment with silver triflate in DCM produced the pentacyclic lactam 12 (61% from 10). Finally, treatment of compound 12 with LiBH3(NH2)16 in THF resulted in removal of the lactam carbonyl, reduction of the imine residue, and conversion of the amide into the corresponding primary alcohol to form (()-limapermidine (1) in 60% yield. The 1 H and 13C NMR spectral data obtained on this material matched those reported5 by Overman et al., and its structure was secured by single-crystal X-ray analysis.14 Ban and co-workers have reported3 that treatment of compound (()-1 with mercuric acetate in 5% acetic acid at 75 °C for 4045 h provides (()-fendleridine in an (15) Toczko, M. A.; Heathcock, C. H. J. Org. Chem. 2000, 65, 2642. (16) Pasumansky, L; Goralski, C. T.; Singaram, B. Org. Process Res. Dev. 2006, 10, 959. (17) See, for example: (a) Wang, X.; Reisinger, C. M.; List, B. J. Am. Chem. Soc. 2008, 130, 6070. (b) Jiang, H.; Holub, N.; Jørgensen, K. A. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20630. (c) Lu, Y.; Zheng, C.; Yang, Y.; Zhao, G.; Zou, G. Adv. Synth. Catal. 2011, 353, 3129. (18) Chen, J.; Chen, J.-J.; Yao, X.; Gao, K. Org. Biomol. Chem. 2011, 9, 5334.
Org. Lett., Vol. 14, No. 22, 2012
unspecified yield. Although we have been unable to reproduce this converison, when the readily derived 1-acetyllimaspermidine was treated under essentially the same conditions then the racemic modification, (()-13, of the natural product 1-acetylaspidoalbidine (the N-acetyl derivative of fendleridine) was obtained in 30% yield (over two steps) (Scheme 2). The 1H and 13C NMR spectral data obtained on this material matched those reported by Boger et al.4 The protocols reported here should be amenable to the enantioselective synthesis of either the (þ)- or ()-forms of the title alkaloids given the now ready availability of both (S,S)- and (R,R)-7-oxabicyclo[4.1.0]heptan-2-one17 and the capacity of the EschenmoserClaisen reaction to faithfully convert, in a predictable manner, chiral nonracemic allylic alcohols into the corresponding γ,δ-unsaturated amides.10 Efforts are also underway to identify reaction conditions whereby compound 8 can be engaged in a reductive cyclization process that affords the trans-ring-fused isomer of compound 9b since such a system could serve as a precursor to kopsihainanines A and B, two unusual alkaloids recently isolated from Kopsia hainanensis.18 Details of the outcomes of such studies will be reported in due course. Acknowledgment. We thank the Australian Research Council and the Institute of Advanced Studies for generous financial support, Dr. Laurent Petit (ANU) for helpful suggestions regarding the synthesis of compound 4, and Professor Dale Boger (Scripps, La Jolla) for providing spectral data on compound (þ)-13. Supporting Information Available. Full experimental procedures; data derived from the single-crystal X-ray analyses of compounds 1, 9a, and 9b; anisotropic displacement ellipsoid plots for compounds 1 and 9b; and 1 H and 13C NMR spectra of compounds (()-1 and 4(()-13. This material is available free of charge via the Internet at http://pubs.acs.org. The authors declare no competing financial interest.
5623
